title: Novel tools to dissect the dynamic regulation of TCR signaling by the kinase Csk and the phosphatase CD45.
abstract: Although the biochemical events induced by T-cell receptor (TCR) triggering have been well studied, both the mediators and function of basal signaling in T cells remain poorly understood. Furthermore, the precise mechanisms by which MHC-peptide interaction with the TCR disrupt the basal equilibrium to induce downstream signaling are also unclear. Here we describe novel approaches to understand the basal state of T cells and the mechanisms of TCR triggering by perturbing regulation of the Src family kinases (SFKs). The SFKs are critical proximal mediators of TCR signaling that are in turn tightly regulated by the tyrosine kinase Csk and the receptor-like tyrosine phosphatase CD45. We have developed a small-molecule analog-sensitive allele of Csk and an allelic series of mice in which expression of CD45 is varied across a broad range. Our studies have unmasked contributions of Csk and CD45 to maintain the basal state of T cells and also suggest that dynamic regulation of Csk may be involved in TCR triggering.
authors.affiliation: Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, UCSF, San Francisco, CA, 94143, USA.
authors.forename: Ying Xim
authors.initials: YX
authors.lastname: Tan
authors.affiliation: Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, UCSF, San Francisco, CA, 94143, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Zikherman
authors.affiliation: Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, UCSF, San Francisco, CA, 94143, USA.|Howard Hughes Medical Institute, UCSF, San Francisco, CA, 94143, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000483:Alleles; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human